Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-β Intermediates Revealing that Self-Assembly Is Required for Aβ-Induced Cytotoxicity

Dityrosine (DiY), via the cross-linking of tyrosine residues, is a marker of protein oxidation, which increases with aging. Amyloid-beta (A beta) forms DiY in vitro and DiY-cross-linked A beta is found in the brains of patientswith Alzheimer disease. Metal- or UV-catalyzed oxidation of A beta 42 results in an increase in DiY cross-links. Using DiY as a marker of oxidation, we compare the self-assembly propensity and DiY cross-link formation for a non-assembly competent variant of A beta 42 (vA beta) with wild-type A beta 42. Oxidation results in the formation of trappedwild-type A beta assemblies with increased DiY cross-links that are unable to elongate further. Assembly-incompetent vA beta and trapped A beta assemblies are non-toxic to neuroblastoma cells at all stages of self-assembly, in contrast to oligomeric, non-cross-linked A beta. These findings point to a mechanism of toxicity that necessitates dynamic self-assembly whereby trapped A beta assemblies and assembly-incompetent variant A beta are unable to result in cell death.